What is the management and diagnosis for a patient with polycythemia (high red blood cell count), hypochromia (low MCV), low mean corpuscular hemoglobin (MCH), and low mean corpuscular hemoglobin concentration (MCHC)?

Diagnostic Approach: Polycythemia Vera with Iron Deficiency

This presentation of high RBC count with microcytosis (low MCV, MCH, MCHC) is highly characteristic of polycythemia vera complicated by iron deficiency, and you should immediately check a serum erythropoietin level followed by JAK2 mutation testing. 1

Initial Diagnostic Considerations

The combination of elevated RBC count with low MCV, MCH, and MCHC creates a distinctive pattern that narrows your differential significantly:

• Polycythemia vera with iron deficiency is the most likely diagnosis when microcytosis accompanies true polycythemia 1, 2
• Microcytosis from iron deficiency is explicitly recognized as a PV-related feature that should prompt diagnostic evaluation even with borderline hematocrit values 1
• Secondary polycythemia with incidental iron deficiency is possible but less common 2
• Thalassemia minor with coincidental polycythemia is rare but must be excluded 2, 3

Diagnostic Algorithm

Step 1: Verify True Polycythemia

• Confirm the hemoglobin/hematocrit is above the 95th percentile for sex and race 1
• Exclude relative polycythemia by ensuring adequate hydration status and repeating CBC 4
• Look for other PV-related features: thrombocytosis, leukocytosis, splenomegaly, aquagenic pruritus, unusual thrombosis (including Budd-Chiari syndrome), or erythromelalgia 1

Step 2: Measure Serum Erythropoietin Level

• A low serum EPO level is highly suggestive of PV (>90% specificity) but sensitivity is only ~70% 1
• PV is unlikely if EPO is elevated; this should redirect you toward secondary polycythemia 1
• A normal EPO level does not exclude PV and warrants further workup 1

Step 3: Assess Iron Status

• Obtain serum ferritin and transferrin saturation 1, 5
• Ferritin <30 μg/L indicates iron deficiency in the absence of inflammation 1, 5
• Transferrin saturation <20% is a sensitive indicator of iron deficiency 5
• Critical pitfall: Iron deficiency in PV can lower the measured RBC mass into the normal range, potentially masking the diagnosis 1

Step 4: Order JAK2 Mutation Testing

• Test for JAK2V617F mutation (exon 14) as first-line 4
• If negative, proceed to JAK2 exon 12 mutation testing 4
• Positive JAK2 mutation with elevated hemoglobin/hematocrit fulfills major WHO diagnostic criteria for PV 4

Step 5: Bone Marrow Examination (if needed)

• Indicated when EPO is low or normal but JAK2 testing is negative or equivocal 1
• Look for characteristic findings: hypercellularity, increased megakaryocytes with clustering, giant megakaryocytes, pleomorphism, and decreased bone marrow iron stores 1
• Bone marrow histology is often diagnostic to an experienced hematopathologist 1

Distinguishing PV from Other Causes

Polycythemia Vera with Iron Deficiency vs. Thalassemia Minor

• RBC size distribution curves reliably distinguish between these entities 2
• Red cell distribution width (RDW) >14.0% with low MCV suggests iron deficiency, while RDW ≤14.0% suggests thalassemia 5
• In thalassemia, the RBC count is typically elevated but not to the degree seen in PV 2, 3
• Hemoglobin electrophoresis can confirm thalassemia trait 1, 3

Secondary Polycythemia with Iron Deficiency

• Four of five patients with secondary polycythemia and microcytosis had their RBC count remain elevated after iron repletion, with MCV normalizing 2
• Evaluate for hypoxic causes: chronic lung disease, sleep apnea, high altitude, cyanotic heart disease 1
• Consider renal causes: hypernephroma, renal artery stenosis, post-renal transplant erythrocytosis 1

Management Approach

If PV is Confirmed:

• Do NOT give iron supplementation initially - this can worsen hyperviscosity and thrombotic risk 1
• Initiate phlebotomy to maintain hematocrit strictly below 45% to reduce thrombotic risk 4
• Start low-dose aspirin as cornerstone therapy to prevent cardiovascular events 4
• Consider cytoreductive therapy (hydroxyurea or interferon-alpha) for high-risk patients (age >60 or prior thrombosis) 4
• Iron supplementation may be considered only after adequate control of erythrocytosis, under close monitoring 1

If Iron Deficiency Anemia Without PV:

• Oral iron supplementation with ferrous sulfate 200 mg three times daily for at least three months after anemia correction 5
• Adding ascorbic acid enhances iron absorption 5
• In adult men and post-menopausal women, gastrointestinal evaluation with upper endoscopy and colonoscopy is mandatory to exclude GI malignancy 5
• Consider small bowel biopsy during endoscopy to rule out celiac disease 5

Critical Pitfalls to Avoid

• Assuming microcytosis always means simple iron deficiency - this combination specifically suggests PV with iron deficiency 1, 2
• Treating with iron before establishing the diagnosis of PV can worsen hyperviscosity and increase thrombotic complications 1
• Normal MCV, MCH, or MCHC values do not exclude iron deficiency, as these parameters have only moderate diagnostic accuracy 6
• Serum ferritin can be falsely elevated in inflammatory states, making diagnosis challenging 1, 5
• Overlooking combined deficiencies (iron with B12 or folate) which can mask microcytosis 1, 7
• Failing to recognize that iron deficiency in PV can lower RBC mass into the normal range, potentially delaying diagnosis 1

Monitoring After Diagnosis

• Repeat CBC after 4-8 weeks if treating iron deficiency 5
• A good response to iron is defined as hemoglobin rise ≥10 g/L within 2 weeks 5
• For confirmed PV, monitor hematocrit regularly to maintain target <45% 4
• Monitor for thrombotic complications, which represent the major cause of morbidity and mortality in PV 1, 4